Mini‐pig urinary bladder function: comparisons of in vitro anticholinergic responses and in vivo cystometry with drugs indicated for urinary incontinence

Abstract

1 Studies of carbachol-induced contractions on mini-pig bladder tissue strips in vitro demonstrated that antagonist drugs produced a rank order of potency similr to that observed in guinea-pig tissues: propantheline .apprxeq. atropine > oxybutynin > dicyclomine > HHSiD > imipramine > terodiline .apprxeq. AF-DX 116. The drugs appeared to show competitive antagonism and the tissues exhibited resistance to complete cholinergic blockade. 2 Cystometry performed in vivo on awake mini-pigs also showed that i.v. cholinergic antagonist produced a dose-dependent depression of preak intravesical bladder pressure (PvesP) during slow filling of the bladder using urethral catheters, with a rank order of potency: atropine > oxybutynin .apprxeq. propantheline > HHSiD .apprxeq. dicyclomine > terodiline. Other parameters of the cystometrogram were unaffected by the antagonists, except for residual volume, which generally increased after drug treatment. 3 Hexahydrosiladifenidol (HHSiD), an ileal-selective competitive muscarinic antagonist, was about as effective as antagonist as the clinically useful drugs oxybutynin or dicyclomine, both in vitro and in vivo, suggesting that HHSiD may have useful therapeutic effects for the treatment of urinary incontinence. 4 Correlation of the rank order of potency for muscarinic antagonism between mini-pigs and guinea-pigs was very high in vitro (r = 0.97, P < 0.05), as was the correlation among the drugs for their ability to depress PvesP of the cystometrogram in vivo (r=0.89, P<0.05). 5 The data suggest a strong similarity between muscarinic receptors and their actions in mini-pig and guinea-pig urinary bladder tissues, and that these species may be useful in examining drug therapies to treat urinary incontinence for widely different classes of chemical compounds, including Ca2+ antagonists, tricyclic antidepressants and cholinergic antagonists.